Development of allele-specific crispr-nuclease gene therapy for late-onset sensorineural hearing impairment in a humanized dfna9 mouse model.

Hearing loss affects 1.57 billion people worldwide and has been listed by the World Health Organisation as a priority disease for research into therapeutic interventions. DFNA9 is the most frequent hereditary disorder in Belgium and the Netherlands causing hearing loss at 20-30 years and evolving towards deafness by 60-70 years. Currently, there is no therapy available. The aim of this project is to develop a gene therapy that can delay or stop the progression of DFNA9 in the pre-symptomatic window of opportunity. Only one of the two copies of the COCH gene (one inherited from either parent), is mutated in DFNA9 and encodes for a toxic protein that affects the aging inner ear. Our therapeutic approach is designed to specifically stop the production of this mutated COCH protein, leaving the patient only with healthy COCH proteins. Earlier research has demonstrated that one healthy COCH gene is sufficient for normal hearing. It is of vital importance that protein production from the healthy COCH gene is not affected. As mutant and healthy COCH only differ by a single nucleotide, high sensitivity and specificity is essential to specifically recognize the mutant COCH gene. To achieve this, we will adapt the genetic manipulation tool "CRISPR-Cas9". This project will provide insight in which approach is most suitable to safely and specifically block the production of mutant COCH proteins and will lay the foundation for continued (pre)clinical development towards clinical trials.

Keywords:HEREDITARY DEAFNESS, GENE THERAPY

Disciplines:Clinical genetics and molecular diagnostics, Genetics, Otology

Project type:Collaboration project